eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Pyruvate Carboxylase Deficiency: Treatment & Medication

Author: Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Coauthor(s): Paul J Benke, MD, PhD, Director of Clinical Genetics, Joe DiMaggio Children's Hospital
Contributor Information and Disclosures

Updated: Nov 6, 2009

Treatment

Medical Care

  • Treatments in patients with pyruvate carboxylase deficiency (PCD) are aimed at stimulating the pyruvate dehydrogenase complex (PDC) and providing alternative fuels. Correction of the biochemical abnormality can reverse some symptoms, but central nervous system damage progresses regardless of treatment.
  • The PDC can provide an alternative pathway for pyruvate metabolism PDC activity can be optimized by cofactor supplementation with thiamine and lipoic acid and administration of dichloroacetate. Increased pyruvate metabolism through this pathway can help reduce the pyruvate and lactate levels.
  • Biotin supplementation is given to help optimize the residual enzyme activity but is usually of little use.
  • Citrate supplementation reduces the acidosis and provides the needed substrate in the citric acid cycle.
  • Aspartic acid supplementation allows the urea cycle to proceed and reduces the ammonia level.
  • One patient reportedly was successfully treated with a continuous nocturnal gastric drip feeding of uncooked cornstarch.
  • Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case by presumably providing a source of acetyl-CoA and anaplerotic propionyl-CoA. However, life expectancy was not prolonged.
  • Orthotopic liver transplantation has reversed the biochemical abnormalities in one patient.2

Consultations

  • Evaluation by an expert in metabolic and genetic disorders is necessary to confirm the diagnosis, guide the appropriate treatment, and determine the prognosis.
  • Genetic counseling for the parents is important in order to determine the risk of recurrence in future pregnancies.

Diet

  • Diet has a small effect on outcome.
  • A high-carbohydrate, high-protein diet may help to maintain an anabolic state and prevent activation of gluconeogenesis.

Medication

Enzyme activator

Dichloroacetate (DCA) sodium is the only drug found to activate the enzyme complex.


Sodium dichloroacetate

Designated as an orphan drug in the United States. Used to treat lactic acidosis. This is a compound that is believed to activate the PDC by inhibiting the inactivating kinase, resulting in decreased lactate production and promotion of pyruvate oxidation.

Adult

30-100 mg/kg/d IV divided bid

Pediatric

Administer as in adults

Reduces urate clearance and may counteract the effect of uricosuric drugs

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Sedation is common; stimulates myocardial contractility; may elevate serum transaminases; polyneuropathy has been reported with long-term administration of DCA; urinary oxalate crystal formation has been reported and is a dose-related phenomenon; DCA is currently an investigational agent and is not commercially available; it is only available through an investigational protocol at this time

Alkalinizing agents

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes, including diabetic coma, diarrhea, kidney disturbances, and shock. Sodium bicarbonate also increases renal clearance of acidic drugs.


Sodium bicarbonate

Bicarbonate can be used to correct the acidosis in chronic and acute settings.

Adult

Acidosis during acute attacks: 1-2 mEq/kg IV infused over 20 min; infusion can be repeated up to q30min prn in an emergency setting but careful monitoring of blood pH must be obtained
Chronic acidosis: 1-3 mEq/kg/d PO qid

Pediatric

Acidosis during acute attacks: Administer as in adults
Chronic acidosis: 2-5 mEq/kg/d PO qid

Sodium bicarbonate inactivates catecholamines, calcium salts, and atropine when mixed together; shown to decrease therapeutic levels of methotrexate, tetracyclines, and salicylates due to urinary alkalinization

Alkalosis; hypernatremia; severe pulmonary edema; hypocalcemia; unknown abdominal pain

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May precipitate hypernatremia, circulatory overload, and hypocalcemia; may cause a metabolic alkalosis; avoid extravasation; carefully monitor arterial or venous blood pH with IV infusion; response to bicarbonate should be checked 10-20 min after infusion; guide repeat treatment with bicarbonate by clinical change in the patient's condition along with laboratory values; take particular care when using with neonates because of increased risk of intraventricular hemorrhage


Citrate solutions (Bicitra, Polycitra)

Several solutions containing citrate with sodium or potassium or both are available as alkalinizing agents. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.

Adult

Chronic acidosis: 1-3 mEq/kg/d PO divided tid/qid

Pediatric

Chronic acidosis: 2-5 mEq/kg/d PO divided tid/qid

Urine alkalinization may decrease serum levels of lithium, chlorpropamide, methenamine, methotrexate, salicylates, or tetracyclines; urine alkalinization may increase serum levels of flecainide, quinidine, or sympathomimetics

Severe renal impairment; acute dehydration

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause hypokalemia, hypernatremia, and/or hyperkalemia depending on the formulation used; formulation should be individually based with consideration of other supplementation and the ability of the patient to tolerate sodium or potassium loads

More on Pyruvate Carboxylase Deficiency

Overview: Pyruvate Carboxylase Deficiency
Differential Diagnoses & Workup: Pyruvate Carboxylase Deficiency
Treatment & Medication: Pyruvate Carboxylase Deficiency
Follow-up: Pyruvate Carboxylase Deficiency
Multimedia: Pyruvate Carboxylase Deficiency
References
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References

  1. Monnot S, Serre V, Chadefaux-Vekemans B, et al. Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum Mutat. May 2009;30(5):734-40. [Medline].

  2. [Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline].

  3. Al-Essa MA, Ozand PT. Manual of Metabolic Disease. ed. Riyadh, Saudi Arabia: King Faisal Specialist Hospital and Research Centre; 1998.

  4. Augereau C, Pham Dinh D, Moncion A. Pyruvate carboxylase deficiencies: complementation studies between "French" and "American" phenotypes in cultured fibroblasts. J Inherit Metab Dis. 1985;8(2):59-62. [Medline].

  5. Bartlett K, Ghneim HK, Stirk JH. Pyruvate carboxylase deficiency. J Inherit Metab Dis. 1984;7 Suppl 1:74-8. [Medline].

  6. De Meirleir L. Defects of pyruvate metabolism and the Krebs cycle. J Child Neurol. Dec 2002;17 Suppl 3:3S26-33; discussion 3S33-4. [Medline].

  7. Garcia-Cazorla A, Rabier D, Touati G, Chadefaux-Vekemans B, Marsac C, de Lonlay P. Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol. Jan 2006;59(1):121-7. [Medline].

  8. Higgins JJ, Glasgow AM, Lusk M. MRI, clinical, and biochemical features of partial pyruvate carboxylase deficiency. J Child Neurol. Oct 1994;9(4):436-9. [Medline].

  9. Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab. Apr 2005;84(4):305-12. [Medline].

  10. Nyhan WL, Khanna A, Barshop BA. Pyruvate carboxylase deficiency--insights from liver transplantation. Mol Genet Metab. Sep-Oct 2002;77(1-2):143-9. [Medline].

  11. Perry TL, Haworth JC, Robinson BH. Brain amino acid abnormalities in pyruvate carboxylase deficiency. J Inherit Metab Dis. 1985;8(2):63-6. [Medline].

  12. Robinson BH. Lactic acidemia and mitochondrial disease. Mol Genet Metab. Sep-Oct 2006;89(1-2):3-13. [Medline].

  13. Roe CR, Mochel F. Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential. J Inherit Metab Dis. Apr-Jun 2006;29(2-3):332-40. [Medline].

  14. Schiff M, Levrat V, Acquaviva C, Vianey-Saban C, Rolland MO, Guffon N. A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation. Mol Genet Metab. Feb 2006;87(2):175-7. [Medline].

  15. Stacpoole PW, Barnes CL, Hurbanis MD. Treatment of congenital lactic acidosis with dichloroacetate [see comments]. Arch Dis Child. Dec 1997;77(6):535-41. [Medline].

  16. Ullrich K, Schmidt H, van Teeffelen-Heithoff A. Glycogen storage disease type I and III and pyruvate carboxylase deficiency: results of long-term treatment with uncooked cornstarch. Acta Paediatr Scand. Jul 1988;77(4):531-6. [Medline].

  17. Van Coster RN, Janssens S, Misson JP. Prenatal diagnosis of pyruvate carboxylase deficiency by direct measurement of catalytic activity on chorionic villi samples. Prenat Diagn. Oct 1998;18(10):1041-4. [Medline].

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Further Reading

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Keywords

pyruvate carboxylase deficiency, PCD, PC, congenital infantile lactic acidosis, intermittent ataxia with lactic acidosis type II, Leigh necrotizing encephalopathy, treatment, diagnosis

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Contributor Information and Disclosures

Author

Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Richard E Frye, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and International Neuropsychological Society
Disclosure: Nothing to disclose.

Coauthor(s)

Paul J Benke, MD, PhD, Director of Clinical Genetics, Joe DiMaggio Children's Hospital
Paul J Benke, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Nothing to disclose.

Medical Editor

Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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